The discovery of the “Achilles heel” protein paves the way for a new class of anti-HIV drugs

Publicado em 16 novembro 2020

The discovery of a possible “Achilles heel” in Nev, the protein essential to HIV and its ability to cause AIDS, paves the way for the development of a new class of drugs against the virus. Researchers have succeeded in showing a structure that binds this protein to another called AP-2 and regulates endocytosis, which is the process by which cells take in substances such as nutrients or pathogens by immersing them in a vesicle.

As a result, it is becoming increasingly clear how Nef was able to sabotage the defense mechanisms of human cells, enable HIV to reproduce and bring the symptoms of AIDS closer together.

In an article Published in a Structural nature and molecular biology (NSMB), PhD candidate Yunnan Januaro and Professor Luis Lambert Pinto da Silva At the Ribeirao Preto College of Medicine of the University of São Paulo (FMRP-USP) in Brazil, he comments on the importance of recent discoveries about this protein.

The researchers succeeded in obtaining the three-dimensional structure between Nef-CD4 and AP-2, showing the contact surfaces and making it possible to conduct further studies designed to produce a molecule that occupies this space to prevent the effects of the protein from progressing. This “picture” could serve as a basis for developing other treatments to combat HIV, ”Silva said FAPESP Agency.

With over 15 years experience in this field, Silva has been invited before NSMB To comment on a study described in the article “The structural basis for downregulation of CD4 by HIV-1 Nef”, Published In the same issue of the journal and with Yonghwa Kwon, a researcher at the University of Massachusetts (USA) as a senior author.

It should be noted that the study by Kwon et al. It provides the structural basis for the cooperative assembly of the AP-2 – Nef – CD4 triple complex and demonstrates that Nef directly links CD4 and AP-2. The study also reveals a structural relationship between Nef-mediated downregulation of CD4 and Nef’s antagonism to major histocompatibility complex I (MHC-I), ”the two Brazilians write in NSMB Article.

According to Silva, NEF has been known to be critical to the progression of the effects of HIV as AIDS progresses. In addition, protein production by the patient’s organism may continue to be treated or whose viral load remains too small to be detected. This has been linked to the comorbidity of the infection. Neve is important, and there are no drugs to target him. “

Since it was discovered that AIDS is caused by HIV nearly 40 years ago, scientists have learned a lot about the complex mechanisms by which the virus attacks the immune system, invades and controls cells, but they have yet to find a way to directly prevent Nef. . They know that Nef is a multifunctional protein with a complex mechanism. It is not part of the HIV structure, but it modifies cells to allow the virus to multiply.

Several classes of antiretroviral drugs work on the immune system to prevent the different stages of the HIV reproduction cycle, reduce the viral load, and even stop disease progression. The most common antiretrovirals include reverse transcriptase inhibitors (nucleoside and non-nucleoside), which disrupt the virus’s use of the reverse transcriptase to transcribe its genetic material and reproduce within defense cells. They also include protease and entrainment inhibitors, which inhibit virus replication and cell invasion, respectively, and entry inhibitors, which prevent the virus from invading defense cells by blocking receptors such as CCR5.

All these drugs have led to remarkable progress in terms of reducing the incidence of disease and death due to AIDS, but viral resistance and the side effects of the drugs require constant research into new ways to combat the virus.

About 38 million people were infected with the virus worldwide in 2019, including 1.8 million children aged 14 or younger, according to the Joint United Nations Program on HIV and AIDS (UNAIDS), which also says 67% They got antiviral treatment. In Brazil, statistics from the Ministry of Health show that about 866,000 people were infected with HIV in 2019.

Other link paths

Silva and his research group at FMRP-USP published a study early this year showing how Nef uses another cell protein, AP-1G2, and the link between the two pathways. The study was Supported by FAPESP.

The group analyzed the effects of Nef on the inner membranes of a host cell, and described the mechanisms by which AP-1G2 uses and sends CD4 to lysosomes (cell organelles containing enzymes that break down proteins and other molecules). This removes them from the cell surface and helps release the virus from the cells to spread the infection.

CD4 is the receptor that HIV uses to invade cells. If it remains on the cell surface, the release of the virus is blocked: and then removed by Nef from the infected cells. “We have indicated the common point between these two tracks,” Silva said. In order to send CD4 and MHC-I to the lysosomes, Nef hijacks a third cellular protein common to both pathways. These results can help other groups demonstrate exactly how Nef interacted with the third protein to define a new target, just as it did with AP-2. “

Silva and his group are currently working on another study, too Supported by FAPESP. The goal is to discover other targets of Nef. “Many ingredients are available. Now someone has to come to put it all together and get this molecule that is able to inhibit Neff.


About the Sao Paulo Research Foundation (FAPESP)

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